Despite the current FDA-approved therapies, the prevalence of type 2 diabetes (T2D) and various other metabolic diseases is reaching epidemic proportions. Globally, 387 million people have overt diabetes, and the prevalence of impaired fasting glucose (precursor to T2D referred to as ?pre-diabetes?) is 26% of the US population. Consequently, T2D and its frequent co-morbidities (high triglycerides, non-alcoholic fatty liver disease / non-alcoholic steatohepatitis [NAFLD/NASH], and cardiovascular disease) increasingly account for a large proportion of global end-stage renal and liver failure, limb amputations, blindness, myocardial infarctions, and strokes. To address this highly unmet need, Potrero Hill Therapeutics, Inc. (?PHT?) is discovering and developing small molecule inhibitors of dihydroceramide desaturase-1 (Des1), a key enzyme which catalyzes the final step in the de novo formation of ceramides, molecules which drive insulin resistance, high triglycerides, fatty liver, and atherosclerosis when produced in excess. Fundamentally, PHT's Des1 inhibitor discovery effort is based upon mounting evidence in rodent disease models implicating ceramides as causal agents of high triglycerides, NAFLD/NASH, diabetes, hypertension, atherosclerosis, and other cardiovascular complications. In this STTR Phase 1 grant, PHT will collaborate with scientists at the University of Utah College of Health to accomplish two aims which will lead to the identification of novel Des1 inhibitor therapeutic candidates: 1) We will synthesize and characterize the potency and drug-like properties of 40-50 compounds; and 2) We will further assess novel Des1 inhibitor activity in a liver cell assay of endogenous ceramide biosynthesis as well as their in vivo pharmacokinetic properties. Ultimately, successful completion of both aims will lead to novel Des1 inhibitor compounds which would be tested in rodent models of insulin resistance to demonstrate in vivo efficacy proof-of-concept.